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A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.

Zhang Q, Zeng SX, Zhang Y, Zhang Y, Ding D, Ye Q, Meroueh SO, Lu H - EMBO Mol Med (2012)

Bottom Line: Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress.Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro.Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.

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A model for INZ action in cancer cellsUpon stress, p53 is significantly acetylated by p300 and thus prevented from ubiquitylation and degradation mediated by MDM2/MDMX. SIRT1 deacetylates p53, not only inhibiting its activity, but also rendering p53 into an ideal substrate for MDM2/MDMX-mediated ubiquitylation and degradation. INZ can induce p53 acetylation and level, hence reactivating p53 by inhibiting SIRT1 deacetylase activity, as SIRT1 is often highly expressed in cancers or cancer cells due to the lack of expression of its repressor HIC-1 via promoter hypermethylation as indicated in dotted lines; Otherwise, in normal cells where its promoter is not hypermethylated, HIC-1 can be induced by p53 to repress SIRT1 expression at the mRNA level in response to stress.
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fig08: A model for INZ action in cancer cellsUpon stress, p53 is significantly acetylated by p300 and thus prevented from ubiquitylation and degradation mediated by MDM2/MDMX. SIRT1 deacetylates p53, not only inhibiting its activity, but also rendering p53 into an ideal substrate for MDM2/MDMX-mediated ubiquitylation and degradation. INZ can induce p53 acetylation and level, hence reactivating p53 by inhibiting SIRT1 deacetylase activity, as SIRT1 is often highly expressed in cancers or cancer cells due to the lack of expression of its repressor HIC-1 via promoter hypermethylation as indicated in dotted lines; Otherwise, in normal cells where its promoter is not hypermethylated, HIC-1 can be induced by p53 to repress SIRT1 expression at the mRNA level in response to stress.

Mentions: Our study as presented here identifies INZ as a novel small molecule that possesses an ability to induce p53 level and activity, consequently leading to p53-dependent apoptosis. As a result, this compound inhibits the growth of xenograft tumours from p53-containing lung and colon cancer cell lines, but exhibits minimum effect on tumours from p53- HCT116 cells. By using a rationale-based strategy and a reverse target-identification approach (identifying the target(s) of a compound after unveiling its cellular phenotype or biological activity), we excavated a likely mechanism that attributes to the activation of p53 by this compound, that is inhibition of SIRT1 activity (Fig 8). Our initial biochemical analyses indicate that INZ does not appear to compete with a substrate for the active site of SIRT1, but might affect the binding of NAD+ to SIRT1 via an uncompetitive mechanism, though this mode of action needs to be further investigated.


A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.

Zhang Q, Zeng SX, Zhang Y, Zhang Y, Ding D, Ye Q, Meroueh SO, Lu H - EMBO Mol Med (2012)

A model for INZ action in cancer cellsUpon stress, p53 is significantly acetylated by p300 and thus prevented from ubiquitylation and degradation mediated by MDM2/MDMX. SIRT1 deacetylates p53, not only inhibiting its activity, but also rendering p53 into an ideal substrate for MDM2/MDMX-mediated ubiquitylation and degradation. INZ can induce p53 acetylation and level, hence reactivating p53 by inhibiting SIRT1 deacetylase activity, as SIRT1 is often highly expressed in cancers or cancer cells due to the lack of expression of its repressor HIC-1 via promoter hypermethylation as indicated in dotted lines; Otherwise, in normal cells where its promoter is not hypermethylated, HIC-1 can be induced by p53 to repress SIRT1 expression at the mRNA level in response to stress.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3376857&req=5

fig08: A model for INZ action in cancer cellsUpon stress, p53 is significantly acetylated by p300 and thus prevented from ubiquitylation and degradation mediated by MDM2/MDMX. SIRT1 deacetylates p53, not only inhibiting its activity, but also rendering p53 into an ideal substrate for MDM2/MDMX-mediated ubiquitylation and degradation. INZ can induce p53 acetylation and level, hence reactivating p53 by inhibiting SIRT1 deacetylase activity, as SIRT1 is often highly expressed in cancers or cancer cells due to the lack of expression of its repressor HIC-1 via promoter hypermethylation as indicated in dotted lines; Otherwise, in normal cells where its promoter is not hypermethylated, HIC-1 can be induced by p53 to repress SIRT1 expression at the mRNA level in response to stress.
Mentions: Our study as presented here identifies INZ as a novel small molecule that possesses an ability to induce p53 level and activity, consequently leading to p53-dependent apoptosis. As a result, this compound inhibits the growth of xenograft tumours from p53-containing lung and colon cancer cell lines, but exhibits minimum effect on tumours from p53- HCT116 cells. By using a rationale-based strategy and a reverse target-identification approach (identifying the target(s) of a compound after unveiling its cellular phenotype or biological activity), we excavated a likely mechanism that attributes to the activation of p53 by this compound, that is inhibition of SIRT1 activity (Fig 8). Our initial biochemical analyses indicate that INZ does not appear to compete with a substrate for the active site of SIRT1, but might affect the binding of NAD+ to SIRT1 via an uncompetitive mechanism, though this mode of action needs to be further investigated.

Bottom Line: Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress.Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro.Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.

Show MeSH
Related in: MedlinePlus